🌸 What is Endometriosis?

• Affects 5–10% of women of reproductive age.
• Caused by tissue similar to the endometrium growing outside the uterus → often on pelvic organs.
• Symptoms: pelvic pain, infertility.
• Diagnosis: usually requires surgery → average 7-year delay.
• Treatments: surgery or hormone therapy (often with side effects).
• Classified by rASRM staging:
  • Stage I/II → superficial lesions, minimal adhesions.
  • Stage III/IV → severe disease with ovarian cysts (endometrioma), scarring, fibrosis, adhesions.

🧬 The Big GWAS Meta-Analysis

• Combined 24 studies with 60,674 cases and 701,926 controls (Europe + East Asia).
• Looked at 10.4 million SNPs.
• Found 42 significant loci (31 new!) with 49 distinct genetic signals.
• Explained ~5% of disease variance in severe (stage III/IV) cases.

👉 Stronger genetic effects in stage III/IV disease (especially ovarian endometriomas).

🔍 Fine-Mapping & Functional Clues

• Identified 6 high-confidence causal variants (all in noncoding regions).
• Many SNPs regulate gene expression (eQTLs) or DNA methylation (mQTLs) in endometrium or blood.
• Genes near hits are enriched in uterus, endometrium, and smooth muscle.

Key candidate genes:

• GDAP1 → neuronal development + dysmenorrhea severity.
• SRP14/BMF → links to hormone bioavailability + pain pathways.
• NGF (nerve growth factor) → affects nerve density around lesions.
• SYNE1/ESR1 → estrogen signaling + pain neurotransmitter regulation.
• FSHB → follicle-stimulating hormone signaling.

😣 Pain & Subphenotypes

• Pain in endometriosis is complex:
  • Stage I/II disease correlated more strongly with pain than stage III/IV (!).
  • Specific SNPs (e.g., in SYNE1/ESR1) linked to dysmenorrhea, dyspareunia, chronic pelvic pain.
  • WT1 locus linked to early-onset menstrual pain (<18 yrs).
• Suggests different genetic bases for pelvic pain vs severe ovarian lesions.

🔗 Comorbidity with Other Conditions

The study used genetic correlation (LD score regression) across traits:

🔥 Inflammatory links

• Asthma (rg=0.17)
• Osteoarthritis (rg=0.24)

🩸 Reproductive traits

• Excessive/irregular menstruation (rg=0.69!)
• Uterine fibroids (rg=0.40)
• Earlier menarche, shorter cycles, earlier menopause, younger age at first birth.

🤕 Pain conditions

Strong overlap with 11 pain traits, including:

• Migraine (rg=0.29)
• Chronic back pain (rg=0.33)
• Multisite chronic pain (MCP) (rg=0.43)
• Dorsalgia (rg=0.45)

🧩 Multitrait Analysis (MTAG)

• Combined GWAS of endometriosis + migraine + MCP.
• Found 52 loci, including 18 new ones not seen in single-trait analysis.
• Some loci shared across all 3:
  • MLLT10, BSN, NGF, SYNE1/ESR1, FSHB.
• Many of these genes are tied to pain perception pathways.

🧠 Big Picture

• Endometriosis genetics involve hormonal, immune, and neuronal pathways.
• Pain isn’t just from lesions but from sensitization of the nervous system, partly genetic.
• Explains why many patients also suffer from migraines, back pain, asthma, or arthritis.
• Opens doors for new treatment targets → maybe even drug repurposing.

🚀 Key Takeaways

1. 42 loci, 49 signals = strongest genetic picture of endometriosis to date.
2. Genetic risk is stronger in severe (stage III/IV) cases.
3. Genes link to hormones, immune responses, and pain maintenance.
4. Strong genetic overlap with other chronic pain and inflammatory diseases.
5. Potential for personalized treatments targeting these shared pathways.